LIFE SUPPORT CRAM

Compare cortical and juxtamedullary nephrons

cortical short, peritubular capillaries

juxtamedullary long, peritubular capillaries AND VASA RECTA

Explain loop of Henle

• Descending limb: Permeable to water but not solutes; water leaves by osmosis, increasing filtrate concentration.

• Ascending limb: Impermeable to water; actively transports Na⁺, K⁺, and Cl⁻ into the medulla, lowering filtrate concentration.

• Countercurrent multiplication: Continuous exchange between limbs amplifies the medullary gradient.

Role of macula densa in the nephron

Chemoreceptor for Na and Cl

Influences renin release in RAAS

Surgical management for incontinence

- Botox into bladder
- Urethral bulking 
- Male sling (artifical urinary sphincter)

Sympathetic innervation for storage phase 

1. Signals sent to sympathetic nuclei in T10-12 
2. Signals travel to bladder via hypogastic nerve 
3. Relaxes detrusor at B3-AR
4. Contracts IUS (internal urethral sphincter) via A1-AR

What are you looking for when investigating a kidney stone in diagnostic tests (bloods)

Haematuria 
Raised WBCs and creatinine in bloods

Symptoms of kidney stones 

- Acute severe flank pain
- Nausea
- Urgency
- Testicular pain 

Somatic control during storage phase 

1. Impulse travels to EUS (external urethral sphincter) via pudendal nerve (roots S2-4)
2. Binds to nicotinic cholinergic receptors on striated muscle -> EUS contracts 
This allows filling and storage of urine - rugae (folds in bladder wall) flatten so the walls can distend and increase urine capacity 

Causes of kidney stones 

- Dehydration
- Too much calcium (hypercalciuria) 
- Alkaline urine 
- Hyperparathyroidism
- UTI
- Gout (high purine diet of meat and seafood)

Medical management for incontinence 

Antimuscarinics to inhibit M3 in urination for detrusor 
Beta-3 agonists to promote SNS on storage phase for detrusor 

Risk factors for a UTI

GENERALLY: BACTERIA AND URINARY STASIS OR IRRITATION OR URETHRA

- Women have a shorter urethra 
- Postmenopausal women have less oestrogen for protection
- Pregnancy has hormonal changes causing urinary stasis 
- Elderly have incomplete bladder emptying 
- Diabetes mellitus has hyperglycemia which encourages bacterual growth
- Urinary obstruction
- Catheters 
- Dehydration means less urine flow and bacteria clearance 
- Frequent sexual actvity irritates urethra 
- Contraception disrupts vaginal flora 
- Poor hygeine means more bacteria 

Explain how the voiding phase works under parasympathetic control 

1. Afferents from spinal cord to pontine micturition centre 
2. When voluntary decision to pee is made, neurones fire to excite the sacral preganglionic neurons 
3. Pelvic nerve stimulated (root S2-4) 
4. Ach released to work on M3, contracting detrusor 
5. Pontine micturition inhibits Onuf's nucleus, decreasing SNS so the IUS relaxes 
6. We consciously reduced EUS contraction so there is distension of urethra 
7. Urine passes 

ANS control on peeing

parasympathetic: pee

sympathetic: store

somatic: choose

How does the proximal convuluted tubule (PCT) reabsorb glucose 

1. a SGLT (sodium-glucose linked transporter) moves sodium and glucose from lumen into the PCT
2. this forms a conc gradient of high Na outside and low Na inside. There is a Na/K ATPase that maintains this (as sodium leaves cell, potassium enters) 
3. at the basolateral membrane, there is a GLUT transporter that binds to the intracellular glucose and passive diffusion carries it from high intracellular to low interstital (see schematic) 
4. glucose then returns to the circulation. anything not reabsorbed will end up in the urine 

How does sodium get reabsorbed in the cells of the PCT

SGLT (sodium glucose linked transporter) and NHE (sodium hydrogen exchanger) get sodium pumped INTO the cell

NaK-ATPase gets sodium out of cell and into circulation 

how is sodium reabsorbed on a molecular level in the thick ascending loop of Henle 

NKCC (Na K Cl symporter) brings sodium in

NaK-ATPase brings Na out and into circulation 

how is sodium reabsorbed on a molecular level in the early distal convoluted tubule (DCT) 

NCC (Na Cl symporter) brings Na in

NaK-ATPase brings Na out and into circulation

how is sodium reabsorbed on a molecular level in the principal cells of the collecting duct

ENaC (epithelial sodium channel) brings Na in

NaK-ATPase brings Na out and into circulation

How does counter-current exchange maintain the hyperosmotic gradient FOR THE LOOP OF HENLE TO KEEP DOING ITS COUNTERCURRENT MECHANISM

The thick ascending loop releases NaCl which will be absorbed by the vasa recta (capillaries surrounding LoH)
It will travel to the other side of the vasa recta and then release it into the medulla - this maintains the gradient for the loop of Henle to work

How can GFR be increased via vasodilation and constriction of afferents/efferents 

dilate afferents 
constrict efferents

Explain autoregulation and myogenic response that controls RBF when there is an dec in blood pressure 

Stretch receptors notice drop in blood pressure 

Vasodilation to increase blood pressure and thus lower GFR and RBF 

What do granular cells secrete, as part of the juxtaglomerular apparatus

renin

equation for GFR

GFR = conc of urine x UFR / conc of plasma

How do macula densa respond to an increased GFR/RBF 

There isnt enough time for the NaCl reabsorption 
1. Greater NaCl load at macula densa 
2. Adenosine release
3. Vasoconstriction of afferent arteriole
4. Lower GFR and RBF 
5. MORE TIME FOR NACL REABSORPTION 

How can GFR be decreased via vasodilation and constriction of afferents/efferents 

constrict affarents

dilate efferents

How do macula densa respond to an decreased GFR/RBF 

1. Lower NaCl load sensed by macula densa 
2. Release of prostoglandins 
3. Vasoconstriction of efferent arterioles 
4. Inc hydrostatic pressure in arterioles
5. Greater GFR and RBF 

Explain autoregulation and myogenic response that controls RBF when there is an inc in blood pressure 

Renal afferent arteriole smooth msucles contain stretch receptors 

Stretch receptors sense this 
Vasoconstriction means less blood pressure in glomerulus so lower RBF and GFR 

Which hormone system is in charge of volume regulation

RAAS

Normal range for ECF osmolarity

285-295

below - dilute

above - conc

Aldosterone secretion can be triggered by RAAS and another ion. Which one?

Increased K+ in plasma 

cause of hypernatremia 

- commonly, water loss
- gain of sodium (rare) 

When given a patient's plasma sodium, how can you calculate their plasma osmolarity 

Assuming glucose and blood-urea-nitrogen is normal,

Sodium conc x 2 = plasma osmolarity 

Explain hypo-osmotic hyponatremia 

'True' hyponatremia 
Water excess 

Which hormone process is responsible for osmoregulation

ADH

Whats hypernatremia 

WATER IMBALANCE
water too low in proportion to the sodium (think of it as a ratio)

Whats pseudo hyponatremia 

When another solute is present in a significant enough quantity that reduces the conc of sodium IN RATIO
which makes the sodium appear low 

What does aldosterone do to the principal cells lining the collecting duct

Na+ reabsorption (and water with it)

K+ excretion

What does aldosterone do to the intercalated cells lining the collecting duct

H+ and HCO3- get excreted out and this maintains electronegativity which avoids acidosis

How is the acid-base balance maintained in the PCT

what value determines hyperkalaemia

more than 5.5mM

cause of respiratory alkalosis

dec CO2

cause of metabolic alkalosis

inc HCO3-

cause of metabolic acidosis

dec HCO3-

cause of respiratory acidosis

inc CO2

differentiate between non anion gap and anion gap metabolic acidosis

non anion gap - theres a normal anion gap so the acidosis is due to loss of HCO3- but Cl- will maintain electroneutrality

anion gap - there are other anions that could be due to excess acid, these anions will maintain electroneutrality

what value determines hypokalaemia

less than 3.5mM

Pharmacological causes of hyperkalaemia

ACEi

ARBs

Hypoaldosteronism

Side effects of ACEi and ARBs

Hyperkalaemia (due to RAAS lowering aldosterone)

Lowers GFR

ACEi causes a dry cough due to bradykinin production

pH equation (basically Henderson-Hasselbach simplified)

ABCD

Acidity = Bicarbonate / Carbon Dioxide

How do loop diuretics work

Thick ascending loop of Henle

Inhibits NKCC so lots of electrolytes and water excreted

How do thiazide diuretics work

In the early DCT

Inhibits NCC so lots of electrolytes and water lost

How do K sparing diuretics work

Blocks ENaC in the principal cells of the CD

Increases sodium excretion without K excretion also

Good to be used in combo with loops or thiazides, alone its a weak one

How do vasopressin receptor antagonists work

Inhibits the action of ADH in the collecting duct

Why do loops and thiazides lead to hypokalaemia

Increases ENaC

lots of sodium reaches the CD that would usually be reabsorbed by now

so it gets reabsorbed in the ENaC, meaning K+ gets excreted and gets low

Why are loops good for heart failure patients

Release of PGI2 (prostacyclins) causes vasodilation

How can loops and thiazides lead to metabolic alkalosis

diuretics cause a drop in blood volume

RAAS activates

Ang II stimulates NHE so we lose H+

How does CKD lead to bone mineral disease (BMD) 

We gain phosphates from our diet. The GI tract filters it and it gets excreted/reabsorbed in the glomerulus. 
CKD has less functioning renal mass so there is phosphate retention.
Phosphate will bind to calcium, forming Ca₃(PO₄)₂ 
This means we have a lower [free Ca²⁺] -> calcium deficiency
The parathyroid gland senses this and makes more PTH (parathyroid hormone) in order to increase [Ca²⁺] (this is secondary hyperparathyroidism) 
This calcium comes from the bones (bone resorption - breakdown of bones for mineral release)

Therefore reduced bone mineral density and patients are more prone to pathological fractures 

How do we classify CKD

CKD-EPI heatmap

level of proteinuria and eGFR dictate staging

4 indications of renal replacement therapy eligibility

1. Refractory hyperkalaemia
2. Metabolic acidosis
3. Uraemia -> shown clinically via unexplainable weight loss, nausea, itchiness, seizures
4. Refractory pulmonary oedema 

Only 1 of these are needed to be eligible 

Define Chronic Kidney Disease (CKD)

Abnormality of kidney structure or function that persists for over 3 months

What does albuminuria suggest pathologically 

If albumin is leaking into urine, there is a strucutural issue with the podocytes or glomerular basement membrane

How does CKD lead to a vitamin D deficiency?

Kidneys produce alpha-hydroxylase which is needed for activating vitamin D 
Less of this enzyme is made so a deficiency occurs 

What are some markers of kidney disease

- Albuminuria
- Haematuria 
- Electrolyte disorder
- Renal histological abnormalities 
- History of kidney transplantation

Why does CKD lead to normochromic-normocytic anaemia 

Kidneys produce erythropoietin but with CKD, there are not enough peritubular cells to do so.
Therefore not enough RBCs produced -> anaemia 

What are the well-validated formulae for eGFR 

MDRD 
CKD-EPI (heat map)

Why does nephrotic syndrome lead to hypercoagulability 

Protein C and S will be lost in heavy proteinuria 
They are important in clotting cascade 
Patient will be more prone to clotting and things like DVT or PE 

Define nephritic syndrome

An abrupt onset of both haematuria and proteinuria for 1-3 days with a decreased GFR 

What value of proteinuria do you need for it to fit the basis for nephrotic syndrome ie be considered heavy 

More than 3.5g a day 

gold standard scan for a kidney stone 

CT with no contrast (CT KUB)

In nephrotic syndrome, you get all 3 of these things. Name them 

1. Heavy proteinuria (more than 3.5g a day)
2. Oedema 
3. Hypoalbuminaemia (less than 30g/L)

Why does nephrotic syndrome lead to oedema 

Hypoalbuminaemia 
Less oncotic pressure 
So fluid will move to the interstitium (leaky tissues) -> oedema 

Normal GFR

90

Investigations for AKI

- Urine analysis for proteinuria, haematuria etc
- ECG for hyperkalaemia 
- Bladder scan to identify obstruction
- Bloods for U+E, FBC, liver function, albumin, creatinine, inflammatory markers such as CRP
- CT KUB for stones 

Define acute kidney injury (AKI)

Abrupt decline in renal function 

What findings in urine analysis are indicative of glomerular disease 

- Proteinuria
- Haematuria
- Red cell casts
- Dysmorphorphic RBCs 

Whats in rapidly progressive GN

Proteinuria and haematuria for days to weeks 

Classifications of AKI

1. Pre-renal: issue with blood vessels (renal artery, vein, afferent, efferent)
2. Renal: nephron issue so filtration issue
3. Post-renal: obstruction of urine flow (ureter, urethra, bladder issue) 

Which criteria can stage AKI

KDIGO

Why does nephrotic syndrome lead to hypercholesterolaemia 

Hypoalbuminaemia 
The liver will try compensate by producing more albumin but it will also produce more lipids
This can lead to patient having high cholesterol

How low does serum albumin need to be for it to count as hypoalbuminaemia under nephrotic syndrome 

Less than 30g/L 

4 principles of glomerular disease 

1. Nephrotic syndrome
2. Nephritic syndrome 
3. Isolated proteinuria/haematuria
4. Rapidly progressive GN 

ST depression pathology

Ischaemia 

Pathology for elevated ST segment

Myocardial infarction

Explain the regulation of iron absorption

Hepcidin inhibits FPN, erythroferrone stops that happening

HIF enhances iron absorbing gene

Effects on the blood caused by G6PD deficiency

Acute haemolysis 
Hb precipitate into Heinz bodies 

Which enzyme deficiency in the glycolysis (Embden-Meyerhof) pathway will affect RBC ATP yield 

Pyruvate kinase 

How does a B12 or folate deficiency affect blood

Megaloblastic (big and immature) anaemia with macroovalocytes (big and oval) and hypersegmented neutrophils 

this is due to nuclear maturation

Which parts of the PPP (pentose phosphate pathway) is disrupted by a G6PD deficiency

NADPH and GSH

Which enzyme deficiency in the Hexose Monophosphate Shunt/Pentose Phosphate pathway affects RBC's ATP yield 

G6PD 

How does erythropoiesis generally work

The kidneys detect low oxygen levels in the blood and release erythropoietin (EPO), a hormone that stimulates erythropoiesis.

What is chronic non-spherocytic haemolytic anaemia 

RBC break down prematurely 

Effects of a pyruvate kinase deficiency for RBCs

- RBC cannot deform shape and then return 
- RBC cannot regulate cation conc via Na/K pump --> to maintain the fluid inside a RBC 


So cells become dehydrated and rigid from losing the fluid 

Chronic non-spherocytic haemolytic anaemia 

Within acquired haemolytic anaemia there is immune and non-immune subgroups. 
What are the types of immune acquired HA?

1. Autoimmune - immune sustem makes antibodies to attack RBC
2. Alloimmune- a blood transfusion causes antibodies to attack RBC
3. Drug induced - Medications causing haemolysis 

How is B12 absorbed 

In ileum, bound to IF (intrinsic factor)

Within acquired haemolytic anaemia there is immune and non-immune subgroups. 
What are the types of non-immune acquired HA?

1. Red cell fragmentation - physical damage to RBCs on an abnormal surface, there are mechanical or physical forces 
2. Infection
3. Physical and chemical agents - drugs or chemical poisoning 

The opposite category to acquired HA is hereditary. 
Name some haemoglobinpathies in this

- Sickle cell disease (abnormal synthesis of B globin chain)
- Thalassaemias (reduced rate of synthesis of normal alpha and beta globins, they remain in ratio to eachother so if one goes down so will the other)

The opposite category to acquired HA is hereditary. 
Name some red cell membrane disorders within this. 

- Hereditary spherocytosis (spherical)
- Hereditary elliptocytosis (abnormal shape) 

The opposite category to acquired HA is hereditary. 
Name some red cell metabolism issues within this, think enzyme deficiencies 

- G6PD deficiency
- PK deficiency 

What is haemolytic anaemia 

Anaemia resulting from an increase in the rate of RBC destruction (haemolysis)